The UC Davis MIND Institute IDDRC proposes a Research Project relevant to the Multi-modal Treatment Approaches theme that spans basic and clinical science and utilizes five of the proposed cores. Recent advances in the neurobiology of fragile X syndrome (FXS) have led to targeted treatments that rescue many phenotypic features in the FMRI knock out (KO) mouse and other animal models (Berry-Kravis et al., 2011; Bhakar et al., 2012; Hagerman et al., 2012). Many of these treatments are based on the mGluRS (metabotropic glutamate receptor 5) theory of FXS, which proposes that absence or reduction of FMRP in the full mutation leads to hypersensitivity of the mGluRS pathway to glutamate, which causes intellectual impairments, seizures, and other features of FXS (Bear et al., 2004; Dolen et al., 2007; Huber et al., 2002; Osterweil et al., 2010). In fact, mGluRS antagonists have proven effective in rescuing several FXS-related phenotypes in rodents (Dolen et al., 2010). In contrast to animal studies, therapeutic approaches targeting mGluRS show only modest efficacy in humans (Berry-Kravis et al., 2012). Three factors have contributed to the human findings, (a) Multiple pathways are affected in FXS; thus, targeting only a single pathway is unlikely to fully correct the complex phenotype. Additional targets must be identified so that a polypharmaceutical approach can be developed, (b) The outcome measures used in many clinical trials are not adequate for detecting subtle but meaningful treatment effects. (3) Important treatment-induced changes in brain function may produce only modest short-term changes in observable behavior in individuals with FXS, who have a history of missed and non-normative learning opportunities prior to treatment. It may be possible, however, to boost the phenotypic effects of a drug by adding a behavioral intervention to take advantage of improved brain function.